Background: Marked changes in the hemostatic system are observed in patients with acute liver failure (ALF) induced by acetaminophen (APAP) overdose. The mechanisms driving these changes are poorly understood, in part, because standard experimental settings of APAP hepatotoxicity (i.e., 300 mg/kg APAP) do not adequately model acute liver failure.

Aims: To define the hemostatic state in experimental settings of liver injury/repair and liver failure.

Methods: Wild-type mice were challenged with APAP (300, 450 or 600 mg/kg, i.p.) or vehicle (saline) and blood and liver samples were collected 24 h after challenge.

Results: There was no obvious difference in centrilobular necrosis across each dose of APAP. However, mice challenged with 600 mg/kg APAP showed clear signs of hepatic dysfunction as direct bilirubin and albumin levels were respectively increased and decreased. Histological changes such as hemorrhage/congestion, hepatocyte vacuolization and sinusoidal perturbation distinguished mice challenged with 600 mg/kg APAP from lower APAP doses. Thrombin generation was reduced in APAP-challenged mice, with only subtle differences observed across doses. Despite this subtle difference, mice challenged with 600 mg/kg APAP displayed profound changes consistent with a consumptive coagulopathy as evidenced by a substantially prolonged prothrombin time, near undetectable levels of plasma fibrinogen, and dramatic elevation in markers of coagulation activation (thrombin anti-thrombin complexes) and fibrinolysis (d-dimer). Ex vivo addition of mouse fibrinogen to restore plasma fibrinogen levels in mice challenged with 600 mg/kg APAP only partially corrected the prolonged prothrombin time. Interestingly, hepatic fibrin(ogen) deposition did not display any connection to APAP dose, whereas hepatic VWF deposition was dramatically increased in mice challenged with 600 mg/kg compared to lower APAP doses.

Conclusions: APAP-induced ALF in mice is associated with profound coagulopathy not evident in standard APAP hepatotoxicity. These results suggest experimental APAP dose-response studies could uncover the mechanistic basis of hemostatic changes observed in ALF patients.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/experimental-acetaminophen-induced-acute-liver-failure-is-associated-with-a-profound-consumptive-coagulopathy/